Is C8B p.Ser555Cys (c.1664C>G) pathogenic?

C8B p.Ser555Cys (c.1664C>G) is classified Uncertain significance in C8B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-12). AlphaMissense: likely pathogenic (0.7066); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with C8B p.Ser555Cys (c.1664C>G)?

C8B p.Ser555Cys (c.1664C>G) is associated with Inborn genetic diseases (ClinVar).

How common is C8B p.Ser555Cys (c.1664C>G) in the general population?

C8B p.Ser555Cys (c.1664C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C8B p.Ser555Cys (c.1664C>G)?

AlphaMissense predicts likely pathogenic (score 0.7066) — an in-silico prediction, not a clinical call.

C8B p.Ser555Cys

c.1664C>G · VCV3483709

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7066 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,896)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7066	likely pathogenic
REVEL	0.398	indeterminate
SaProt	LLR -11.54	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,613,896). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: C8B
Protein: p.Ser555Cys
Coding: c.1664C>G
MANE Select: NM_000066
Type: single nucleotide variant
Location: chr1:56929516 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 555: the tsp type-1 2 domain; a UniProt-annotated variant site (in c8d2)

Full C8B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C8B p.Ala21Thr Uncertain significance ★★ ⚠ same condition
C8B p.Ala446Val Uncertain significance ★★ ⚠ same condition
C8B p.Arg136Cys Uncertain significance ★★ ⚠ same condition
C8B p.Arg136His Uncertain significance ★★ ⚠ same condition
C8B p.Arg156Gly Uncertain significance ★★ ⚠ same condition
C8B p.Arg296Cys Uncertain significance ★★ ⚠ same condition
C8B p.Arg296His Uncertain significance ★★ ⚠ same condition
C8B p.Arg428Gln Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/c8b-p-ser555cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown